US4010179A - 1-(Para-substituted-phenyl)-1H-tetrazoles - Google Patents
1-(Para-substituted-phenyl)-1H-tetrazoles Download PDFInfo
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- US4010179A US4010179A US05/630,563 US63056375A US4010179A US 4010179 A US4010179 A US 4010179A US 63056375 A US63056375 A US 63056375A US 4010179 A US4010179 A US 4010179A
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- sup
- tetrazole
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- -1 1-(Para-substituted-phenyl)-1H-tetrazoles Chemical class 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- 239000004599 antimicrobial Substances 0.000 abstract description 4
- 230000000118 anti-neoplastic effect Effects 0.000 abstract description 2
- 230000000845 anti-microbial effect Effects 0.000 abstract 1
- 241000699670 Mus sp. Species 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 238000011282 treatment Methods 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 13
- 230000004083 survival effect Effects 0.000 description 13
- 238000011081 inoculation Methods 0.000 description 12
- YJIRLMVEJIMKHN-UHFFFAOYSA-N 1-[4-(fluoromethylsulfonyl)phenyl]tetrazole Chemical compound C1=CC(S(=O)(=O)CF)=CC=C1N1N=NN=C1 YJIRLMVEJIMKHN-UHFFFAOYSA-N 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 150000003536 tetrazoles Chemical class 0.000 description 9
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- FGPICMKHZIPYKJ-UHFFFAOYSA-N 1-[4-(difluoromethylsulfanyl)phenyl]tetrazole Chemical compound C1=CC(SC(F)F)=CC=C1N1N=NN=C1 FGPICMKHZIPYKJ-UHFFFAOYSA-N 0.000 description 6
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 6
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- 229960002949 fluorouracil Drugs 0.000 description 6
- 229960000485 methotrexate Drugs 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000011156 evaluation Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000012216 screening Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 229920001817 Agar Polymers 0.000 description 4
- 239000008272 agar Substances 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 239000000902 placebo Substances 0.000 description 4
- 229940068196 placebo Drugs 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- IIGBNXKCYATMMX-UHFFFAOYSA-N 1-[4-(difluoromethylsulfonyl)phenyl]tetrazole Chemical compound C1=CC(S(=O)(=O)C(F)F)=CC=C1N1N=NN=C1 IIGBNXKCYATMMX-UHFFFAOYSA-N 0.000 description 3
- CPCRFCZFSBAGNT-UHFFFAOYSA-N 1-[4-(fluoromethylsulfanyl)phenyl]tetrazole Chemical compound C1=CC(SCF)=CC=C1N1N=NN=C1 CPCRFCZFSBAGNT-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 238000011765 DBA/2 mouse Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000003304 gavage Methods 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 3
- KLOJLBUVPJJOHL-UHFFFAOYSA-N 1-[4-(fluoromethylsulfinyl)phenyl]tetrazole Chemical compound C1=CC(S(=O)CF)=CC=C1N1N=NN=C1 KLOJLBUVPJJOHL-UHFFFAOYSA-N 0.000 description 2
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Substances C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 241000588770 Proteus mirabilis Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- IPFPHIYPZZMUAK-UHFFFAOYSA-N 1-[4-(difluoromethylsulfinyl)phenyl]tetrazole Chemical compound C1=CC(S(=O)C(F)F)=CC=C1N1N=NN=C1 IPFPHIYPZZMUAK-UHFFFAOYSA-N 0.000 description 1
- ODJCIHKBMUREOC-UHFFFAOYSA-N 4-(difluoromethylsulfanyl)aniline Chemical compound NC1=CC=C(SC(F)F)C=C1 ODJCIHKBMUREOC-UHFFFAOYSA-N 0.000 description 1
- IQLOANPEUUNIFI-UHFFFAOYSA-N 4-(fluoromethylsulfanyl)aniline Chemical compound NC1=CC=C(SCF)C=C1 IQLOANPEUUNIFI-UHFFFAOYSA-N 0.000 description 1
- UFDOIGNCXLLTII-UHFFFAOYSA-N 4-(fluoromethylsulfonyl)aniline Chemical compound NC1=CC=C(S(=O)(=O)CF)C=C1 UFDOIGNCXLLTII-UHFFFAOYSA-N 0.000 description 1
- 238000012935 Averaging Methods 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 101100386054 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CYS3 gene Proteins 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 238000009640 blood culture Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 239000010730 cutting oil Substances 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000000295 fuel oil Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000002453 shampoo Substances 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 101150035983 str1 gene Proteins 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 239000001974 tryptic soy broth Substances 0.000 description 1
- 108010050327 trypticase-soy broth Proteins 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
Definitions
- This invention relates to new organic compounds and, more particularly, is concerned with novel 1-phenyl-1H-tetra-zoles substituted in the para-position of the phenyl moiety with various sulfur and fluorine containing functional groups.
- the novel compounds of the present invention may be represented by the following general formula: ##STR1## wherein Z is fluoromethylthio, fluoromethylsulfinyl, fluoromethylsulfonyl, difluoromethylthio, difluoromethylsulfinyl or difluoromethylsulfonyl.
- This invention is also concerned with novel methods of preparing these compounds.
- novel compounds of the present invention are obtainable as white to pale yellow crystalline materials having characteristic melting points and absorption spectra and which may be purified by recrystallization from common organic solvents such as methanol, ethanol, dimethylformamide, acetone, chloroform, ethyl acetate and the like. They are appreciably soluble in non-polar organic solvents such as diethyl ether, benzene, toluene, and the like but are relatively insoluble in water.
- novel compounds of the present invention are useful as antimicrobial agents and possess broad spectrum activity in vivo against Gram-negative and Gram-positive bacteria. These new antimicrobial agents are thereby potentially useful as therapeutic agents in treating bacterial infections in mammals. They are also useful as additives to materials which are subject to microbial deterioration such as cutting oils and fuel oils. They may also be incorporated in soaps, shampoos, and topical compositions for the treatment of wounds and burns. The usefulness of these new antimicrobial agents was demonstrated by their ability to control systemic lethal infections in mice in the following test procedure.
- TSP trypticase soy broth
- test compounds were administered in a single 0.5 ml. oral tubing dose in 0.2% aqueous agar immediately after infection at the indicated levels.
- results are set forth in Table II below as percent effectiveness (alive/total) at 2 days post infection for each dosage level.
- novel compounds of the present invention possess antineoplastic activity which was demonstrated by the following test procedure.
- Tests for antitumor activity were conducted in male or female BDF 1 (C 57 BL/ 6 ⁇ DBA/ 2 ) or CDF 1 (Balb/ c ⁇ DBA/ 2 ) mice weighing 16-20 grams. Mice were inoculated intraperitoneally (IP) with 10 5 /0.25 ml. cells of lymphoid leukemia L1210. The tumor line is maintained by weekly IP passages in DBA/ 2 mice.
- IP intraperitoneally
- the compounds evaluated were 1-(p-fluoromethylsulfonylphenyl)tetrazole; 1-[p-(difluoromethylsulfonyl)-phenyl]-1H-tetrazole and 1-[p-(difluoromethylthio)phenyl]-1H-tetrazole.
- the vehicle employed for the administration of the compounds was 0.2% agar (Difco) in physiological saline.
- the compounds were administered IP or by gavage in a volume of 0.5 ml. per mouse.
- the various treatment regimens utilized with the compounds are noted in the tables.
- the activity of the compounds was evaluated by comparing the mean survival time (MST) of the treated mice to the MST of non-treated controls. A compound was considered active if an increase in MST of ⁇ 25% was achieved among the treated animals*.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
This disclosure describes compounds of the class of 1-(para-substituted-phenyl)-1H-tetrazoles which possess anti-microbial and anti-neoplastic activity.
Description
This application is a continuation-in-part of our copending application Ser. No. 470,083, filed May 15, 1974, now abandoned.
This invention relates to new organic compounds and, more particularly, is concerned with novel 1-phenyl-1H-tetra-zoles substituted in the para-position of the phenyl moiety with various sulfur and fluorine containing functional groups. The novel compounds of the present invention may be represented by the following general formula: ##STR1## wherein Z is fluoromethylthio, fluoromethylsulfinyl, fluoromethylsulfonyl, difluoromethylthio, difluoromethylsulfinyl or difluoromethylsulfonyl. This invention is also concerned with novel methods of preparing these compounds.
The novel compounds of the present invention are obtainable as white to pale yellow crystalline materials having characteristic melting points and absorption spectra and which may be purified by recrystallization from common organic solvents such as methanol, ethanol, dimethylformamide, acetone, chloroform, ethyl acetate and the like. They are appreciably soluble in non-polar organic solvents such as diethyl ether, benzene, toluene, and the like but are relatively insoluble in water.
The novel compounds of the present invention are useful as antimicrobial agents and possess broad spectrum activity in vivo against Gram-negative and Gram-positive bacteria. These new antimicrobial agents are thereby potentially useful as therapeutic agents in treating bacterial infections in mammals. They are also useful as additives to materials which are subject to microbial deterioration such as cutting oils and fuel oils. They may also be incorporated in soaps, shampoos, and topical compositions for the treatment of wounds and burns. The usefulness of these new antimicrobial agents was demonstrated by their ability to control systemic lethal infections in mice in the following test procedure.
The animals used were Carworth Farms CF-1 strain female mice approximately 6 weeks old and averaging 18-22 grams in weight. Infections were produced by intraperitoneal injections of a 0.5 ml. volume (a lethal dose) of a trypticase soy broth (TSP) dilution (as indicated in Table I) of a 5 hour TSP blood culture of the microorganisms listed in Table I below.
TABLE I
______________________________________
TSP dilution of a
Microorganisms 5 hour TSP culture
______________________________________
Proteus mirabilis 1:40
ATCC 4671
Escherichia coli 311
10.sup.-.sup.3
______________________________________
The test compounds were administered in a single 0.5 ml. oral tubing dose in 0.2% aqueous agar immediately after infection at the indicated levels. The results are set forth in Table II below as percent effectiveness (alive/total) at 2 days post infection for each dosage level.
TABLE II
______________________________________
Dosage Level Alive/Total with Escherichia coli
(mg./kg. of body weight)
(A) (B)
______________________________________
128 4/5 5/5
64 3/5 3/5
32 2/5 1/5
16 1/5 2/5
8 1/5 0/5
______________________________________
Infected Non-treated
Controls 5/20
______________________________________
Alive/Total with Proteus mirabilis
(A) (B)
128 5/5 4/5
64 5/5 2/5
32 3/5 2/5
16 1/5 0/5
8 1/5 0/5
______________________________________
Infected Non-treated
Controls 2/20
______________________________________
(A) 1-[p-(difluoromethylthio)phenyl]-1H-tetrazole
(B) 1-[p-(difluoromethylsulfonyl)phenyl]-1H-tetrazole
The novel compounds of the present invention possess antineoplastic activity which was demonstrated by the following test procedure.
Tests for antitumor activity were conducted in male or female BDF1 (C57 BL/6 × DBA/2) or CDF1 (Balb/c × DBA/2) mice weighing 16-20 grams. Mice were inoculated intraperitoneally (IP) with 105 /0.25 ml. cells of lymphoid leukemia L1210. The tumor line is maintained by weekly IP passages in DBA/2 mice. The compounds evaluated were 1-(p-fluoromethylsulfonylphenyl)tetrazole; 1-[p-(difluoromethylsulfonyl)-phenyl]-1H-tetrazole and 1-[p-(difluoromethylthio)phenyl]-1H-tetrazole. The vehicle employed for the administration of the compounds was 0.2% agar (Difco) in physiological saline. The compounds were administered IP or by gavage in a volume of 0.5 ml. per mouse. The various treatment regimens utilized with the compounds are noted in the tables.
The activity of the compounds was evaluated by comparing the mean survival time (MST) of the treated mice to the MST of non-treated controls. A compound was considered active if an increase in MST of ≧25% was achieved among the treated animals*.
TABLE III
______________________________________
Effect of 1-(p-fluoromethylsulfonylphenyl)tetrazole
Against the L1210 Tumor in Mice.sup.1
(Intraperitoneal Treatment)
______________________________________
Average Day
% Increase in
Compound Dose.sup.2
of Death.sup.3
Survival Time.sup.4
______________________________________
1-(p-fluoromethyl-
sulfonylphenyl)tetra-
zole 100 11.2 42
50 14.4 82
25 11.5 46
Methotrexate 1.8 14.6 85
Control.sup.5
-- 7.9 --
______________________________________
.sup.1 CD.sub.2 F.sub.1, female mice inoculated IP with 10.sup.5 L1210
cells per mouse, 10 mice per group.
.sup.2 1-(p-fluoromethylsulfonylphenyl)tetrazole inoculated IP, daily,
from the 1st through the 9th day after inoculation of tumor cells.
Methotrexate inoculated IP, daily, from day 4 until day of death.
.sup.3 100% mortality among treated and control mice.
.sup.4 National Cancer Institute screening protocols require a minimal 25
increase in survival time for a compound to be considered for further
evaluation.
.sup.5 Placebo-treated (0.2% Noble agar in saline) from day 1 through day
9 after inoculation of tumor cells.
TABLE IV
__________________________________________________________________________
Effect of Treatment Schedule on the Activity of
1-(p-fluoromethylsulfonylphenyl)tetrazole Against
L1210 in Mice.sup.1
(Intraperitoneal Treatment)
__________________________________________________________________________
Day of Treatment
following Average Day
% Increase in
Compound Dose Inoculation of Tumor.sup.2
of Death.sup.3
Survival Time.sup.4
__________________________________________________________________________
1-(p-fluoromethylsul-
200 1 9.8 15
fonylphenyl)tetrazole
100 1 9.2 8
50 1 8.9 4
1-(p-fluoromethylsul-
200 2,6 12.5 47
fonylphenyl)tetrazole
100 2,6 10.3 21
50 2,6 9.1 7
1-(p-fluoromethylsul-
100 1,5,9 11.8 39
fonylphenyl)tetrazole
50 1,5,9 9.5 12
Methotrexate
1.8
15.2TR2## 79
Control.sup.5 8.5
__________________________________________________________________________
.sup.1 CD.sub.2 F.sub.1 female mice inoculated with 10.sup.5 L1210 cells
per mouse; 10 mice per group.
.sup.2 1-(p-fluoromethylsulfonylphenyl)tetrazole and methotrexate
inoculated IP on the indicated days following inoculation of L1210 cells.
.sup.3 100% mortality among treated and control mice.
.sup.4 National Cancer Institute screening protocols require a minimal 25
increase in survival time for a compound to be considered for further
evaluation.
.sup.5 Placebo-treated on day 1, 5 and 9 following inoculation of L1210
cells.
TABLE V
__________________________________________________________________________
Effect of Treatment Schedule on the Activity of 1-(p-fluoromethyl-
sulfonylphenyl)tetrazole Against L1210 in Mice.sup.1
(Oral Treatment)
__________________________________________________________________________
Day of Treatment
Dose Following Inoculation
Average Day
% Increase in
Compound (mg./kg.)
of Tumor.sup.2
of Death.sup.3
Survival Time.sup.4
__________________________________________________________________________
1-(p-fluoromethyl-
sulfonylphenyl)-
800 1 11.9 29
tetrazole 400 1 12.0 30
1-(p-fluoromethyl-
400 2,6 11.1 21
sulfonylphenyl)-
200 2,6 13.5 47
tetrazole 100 2,6 11.5 25
1-(p-fluoromethyl-
400 1,5,9 10.4 13
sulfonylphenyl)-
200 1,5,9 12.1 32
tetrazole 100 1,5,9 11.3 23
Methotrexate
1.8
17.1TR3## 86
Control.sup.5 9.2
__________________________________________________________________________
.sup.1 BDF.sub.1 female mice inoculated with 10.sup.5 L1210 cells per
mouse; 10 mice per group.
.sup.2 1-(p-fluoromethylsulfonylphenyl)tetrazole administered by gavage
and methotrexate IP on the indicated days following inoculation of L1210
cells.
.sup.3 100% mortality among treated and control mice.
.sup.4 National Cancer Institute screening protocols require a minimal 25
increase in survival time for a compound to be considered for further
evaluation.
.sup.5 Placebo-treated on day 1, 5 and 9 following inoculation of L1210
cells.
TABLE VI
__________________________________________________________________________
Effect of 1-(p-fluoromethylsulfonylphenyl)tetrazole Against
the L1210 Tumor in Mice.sup.1
(Oral Treatment)
__________________________________________________________________________
Dose Average Day
% Increase in
Compound (mg./kg.).sup.2
of Death.sup.3
Survival Time.sup.4
__________________________________________________________________________
1-(p-fluoromethylsul-
200 12.2 27
fonylphenyl)tetrazole
100 >14.8 >54
50 13.4 34
Cytoxan 50 14.2 42
25 11.8 18
5-Fluorouracil
20 14.6 52
Control.sup.5 9.6
__________________________________________________________________________
.sup.1 CD.sub.2 F.sub.1 female mice inoculated IP with 10.sup.5 L1210
cells per mouse; 5 mice per group.
.sup.2 1-(p-fluoromethylsulfonylphenyl)tetrazole administered by gavage,
daily, from the 1st through the 9th day after inoculation of tumor cells.
5-fluorouracil inoculated IP, daily, from day 1 until day 9.
.sup.3 100% mortality among treated and control mice with the exception o
a single survivor (1/5) in the group treated orally with 100 mg./kg./day
of 1-(p-fluoromethylsulfonylphenyl)tetrazole.
.sup.4 National Cancer Institute screening protocols require a minimal 25
increase in survival time for a compound to be considered for further
evaluation.
.sup.5 Placebo-treated (0.2% Noble agar in saline) from day 1 through day
9 after inoculation of tumor cells.
TABLE VII
__________________________________________________________________________
Effect of Treatment Schedule on the Activity of 1-[p-(difluoromethyl-
sulfonyl)-phenyl]-1H-tetrazole Against L1210 in Mice.sup.1
(Intraperitoneal Treatment)
Day of Treatment
Dose Following Inocula-
Mean Survival
% Increase in
Compound (mg./kg.)
tion of Tumor.sup.2
Time Survival Time.sup.3
__________________________________________________________________________
1-[p-(difluoromethyl-
200 2,6 11.6 36
sulfonyl)-phenyl]-1H-
100 2,6 12.2 43
tetrazole 50 2,6 15.7 81
25 2,6 10.6 25
5-Fluorouracil
60 2,6 >17.8 >109
200 1,3,9 9.8 13
100 1,3,9 11.6 33
50 1,3,9 13.4 54
25 1,3,9 10.6 22
5-Flourouracil
60 1,3,9 >17.0 >100
100
7.4TR4## 0
50
10.8R5## 27
25
12.4R6## 46
5-Flourouracil
20
>18.07## >112
Control 8.5
__________________________________________________________________________
.sup.1 BDF.sub.1 Female mice inoculated with 10.sup.5 L1210 cells per
mouse; 5 mice per group.
.sup.2 Drugs administered IP in volume of 0.5 ml. on indicated days
following inoculation of L1210 cells.
.sup.3 National Cancer Institute screening protocols require a minimal 25
increase in survival time for a compound to be considered for further
evaluation.
TABLE VIII
__________________________________________________________________________
Activity of 1-[p-(difluoromethylthio)phenyl]-1H-tetrazole
Against L1210 in Mice.sup.1
__________________________________________________________________________
Dose Treatment
Mean Survival
% Increase
Compound
(mg./kg.)
Schedule-Days.sup.2
Time-Days
In MST
__________________________________________________________________________
1-[p-(difluoro-
100 1 thru 9
8.4 <1
methylthio)-
50 1 thru 9
13.8 44
phenyl]-1H-tetra-
25 1 thru 9
12.8 33
zole
5-Fluorouracil
20 14.4 50
Control -- 9.6
__________________________________________________________________________
.sup.1 CDF.sub.1 female mice inoculated with 10.sup.5 L1210 cells per
mouse; 5 mice per group.
.sup.2 Drugs administered IP in a volume of 0.5 ml. on days 1 through 9
following inoculation of L1210 cells.
The invention will be described in greater detail in conjunction with the following specific examples.
A mixture of p-(difluoromethylthio)aniline (4.0 g.), sodium azide (4.0 g.), triethyl orthoformate (25 ml.), and acetic acid (25 ml.) was heated at 95° C. for 4.5 hours and then evaporated at reduced pressure. The residue was diluted with water, filtered, dried and recrystallized from ethyl acetate:hexane to give crystals, m.p. 94°-97° C.
1-[p-(Difluoromethylthio)phenyl]-1H-tetrazole (1.0 gram) was added to a cold mixture of 5 ml. of concentrated sulfuric acid and 5 ml. of concentrated nitric acid and stirred for 40 minutes in the cold, then for 40 minutes at room temperature. The reaction mixture was poured onto ice and extracted with ethyl acetate. The ethyl acetate solution was extracted with water, dried over magnesium sulfate, and evaporated to afford an oil which was crystallized from ethyl acetate-hexane. Two recrystallizations from the same solvents gave 143 mg. of product, m.p. 109°-112° C.
A mixture of 1-[p-(difluoromethylthio)phenyl]-1H-tetrazole (2.0 g.), 10 ml. of 30% of hydrogen peroxide, and 40 ml. of acetic acid was heated on a steambath for 4 hours, then diluted with 250 ml. of water. The crystalline product was collected, dried, and recrystallized from ethyl acetate:hexane to give the product, m.p. 162°-164° C.
In accordance with the procedure described in Example 1, treatment of p-(fluoromethylthio)aniline with triethylorthoformate and sodium azide furnishes the 1-[p-(fluoromethylthio)phenyl]-1H-tetrazole.
Treatment of 1-[p-(fluoromethylthio)phenyl]-1H-tetrazole with sulfuric acid and nitric acid by the procedure described in Example 2 is productive of the 1-[p-(fluoromethylsulfinyl)phenyl]-1H-tetrazole.
A mixture of p-(fluoromethylsulfonyl)aniline (0.85 g.), sodium azide (1.5 g.), triethyl orthoformate (10 ml.), and acetic acid (10 ml.) was heated at 85° C. for 5 hours and then evaporated at reduced pressure. The resulting residue was slurried in water and the insoluble solid filtered, dried, and recrystallized from ethyl acetate to give the product m.p. 171°-173° C. dec.
Claims (7)
1. A compound of the formula: ##STR8##wherein Z is selected from the group consisting of fluoromethylthio, difluoromethylthio, fluoromethylsulfinyl, difluoromethylsulfinyl, fluoromethylsulfonyl and difluoromethylsulfonyl.
2. The compound according to claim 1 wherein Z is fluoromethylthio.
3. The compound according to claim 1 wherein Z is difluoromethylthio.
4. The compound according to claim 1 wherein Z is fluoromethylsulfinyl.
5. The compound according to claim 1 wherein Z is difluoromethylsulfinyl.
6. The compound according to claim 1 wherein Z is fluoromethylsulfonyl.
7. The compound according to claim 1 wherein Z is difluoromethylsulfonyl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/630,563 US4010179A (en) | 1974-05-15 | 1975-11-10 | 1-(Para-substituted-phenyl)-1H-tetrazoles |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US47008374A | 1974-05-15 | 1974-05-15 | |
| US05/630,563 US4010179A (en) | 1974-05-15 | 1975-11-10 | 1-(Para-substituted-phenyl)-1H-tetrazoles |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US47008374A Continuation-In-Part | 1974-05-15 | 1974-05-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US4010179A true US4010179A (en) | 1977-03-01 |
Family
ID=27042965
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US05/630,563 Expired - Lifetime US4010179A (en) | 1974-05-15 | 1975-11-10 | 1-(Para-substituted-phenyl)-1H-tetrazoles |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US4010179A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3767667A (en) * | 1971-09-21 | 1973-10-23 | Fujisawa Pharmaceutical Co | Process for preparing 1h-tetrazole compounds |
| US3830928A (en) * | 1972-06-09 | 1974-08-20 | Merck & Co Inc | Substituted phenyltetrazoles as coccidiostats |
-
1975
- 1975-11-10 US US05/630,563 patent/US4010179A/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3767667A (en) * | 1971-09-21 | 1973-10-23 | Fujisawa Pharmaceutical Co | Process for preparing 1h-tetrazole compounds |
| US3830928A (en) * | 1972-06-09 | 1974-08-20 | Merck & Co Inc | Substituted phenyltetrazoles as coccidiostats |
Non-Patent Citations (1)
| Title |
|---|
| Chem. Abstr., vol. 43, 1864-1865, (1949). * |
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